Mois : mai 2024

A vast new study connects plant-based diets with various health benefits, including in cardiovascular diseases and cancer [1].

What exactly is healthy eating?

Diet is one of the most powerful anti-aging interventions available today, but nutrition is also an extremely hard topic to analyze. Food we ingest contains tens of thousands of nutrients, and numerous confounding factors are at play. Most knowledge on this topic comes from populational studies, although many randomized controlled trials have been conducted as well. A new umbrella review seeks to add to our understanding of the effects of plant-based diets on cardiovascular diseases and cancer – two primary causes of death and disability worldwide.

At the beginning of their paper, the researchers note that the deleterious effects of “suboptimal diets”, which are rich in processed foods, salt, refined grains, and sugar, are well-known [2]. Avoiding those is a low bar, but then there is another choice: is it better to eat a plant-based diet, a well-balanced Mediterranean diet, or a ketogenic diet?

Numerous studies have suggested that plant-based diets may be superior to carnivorous or omnivorous ones [3]. On the other hand, concerns exist about nutrient and vitamin deficiencies. While this vast review does not give a definitive answer, it certainly brings together a lot of evidence.

Lipid profiles

This review starts with total cholesterol, an important metric of cardiovascular health. In general, the included studies and reviews found substantial decreases in total cholesterol in people on plant-based diets (both vegan and vegetarian) compared to a variety of other diets. One study found that the effect was even larger for people with high BMI.

Results for high-density lipoprotein cholesterol (HDL-C, which is usually considered beneficial) were less definitive. Several reviews found no difference between vegetarians and omnivores, both in normal weight and overweight people. However, another one, based on 51 studies, reported a slight advantage for plant-based diets.

Low-density lipoprotein cholesterol (LDL-C, which is usually considered harmful) is often considered more important for cardiovascular health than HDL-C. Seven out of ten relevant reviews found that vegetarian diets were associated with significantly lower levels of LDL-C, both in the general population and in diabetic patients. Four other reviews confirmed this for vegan diets compared to omnivores.

Most studies found that vegetarians had significantly reduced triglycerides compared to omnivores. However, one review did not find noticeable differences, and another one’s results were the opposite, that triglyceride levels in vegetarians were higher compared to meat eaters. One of the two reviews that dealt specifically with vegans reported a significant decrease in triglycerides versus omnivores, but the other one did not.

Three reviews among those analyzed had dealt with full lipid profiles rather than singular metrics such as triglycerides or LDL-C. This approach reduced the measurement and reporting differences between studies. All of them found significantly lower levels of total cholesterol, HDL-C, and LDL-C in subjects who followed plant-based diets.

Glucose metabolism and inflammation

Practically all relevant studies agreed on the benefits of plan-based diets for glucose metabolism. The researchers cited lower fasting blood glucose, lower glycated hemoglobin (HbA1c), which is a long-term metric of glucose control, and lower incidence of diabetes.

C-reactive protein (CRP) is the most popular marker of inflammation. Here, too, the results were almost unanimous, with all but one review showing significant CRP reductions in vegans and vegetarians compared to omnivores. Even in that remaining review, lower CRP was recorded for people who were on a vegetarian diet for more than two years.

Cardiovascular disease and cancer

In terms of blood pressure, vegans and vegetarians were again on top, with most studies reporting considerably less both systolic and diastolic blood pressure compared to the general population. One study also found a 33% decrease in the prevalence of hypertension. However, some studies failed to detect a significant difference.

Many studies considered the prevalence of cardiovascular and cerebrovascular events, with most finding diminished risks for plant-based diets. Generally, the effect was more pronounced for heart disease and less so for cerebrovascular outcomes. One study suggested that plant-based diets were advantageous for secondary prevention of cardiovascular diseases, and another one reported that the positive effects were greater in participants who had picked plant-based diets earlier in life.

The researchers also delved into cancer incidence. One review found an 8% reduction in overall cancer risk for vegetarians and 15% for vegans, compared to omnivores. Across all studies, the results were heterogeneous, with some reporting no significant associations, but overall, the risk of colorectal cancer seems to be the one most attenuated by plant-based diets.

Analyzing vast umbrella reviews can be difficult due to the heterogeneity in the design and quality of the included studies. However, this review did include many studies of relatively high quality. Importantly, while some of the studies found no significant correlations between health benefits and plant-based diets, virtually none reported negative associations.

Literature

[1] Capodici, A., Mocciaro, G., Gori, D., Landry, M. J., Masini, A., Sanmarchi, F., … & Guaraldi, F. (2024). Cardiovascular health and cancer risk associated with plant based diets: An umbrella review. PloS one, 19(5), e0300711.

[2] Afshin, A., Sur, P. J., Fay, K. A., Cornaby, L., Ferrara, G., Salama, J. S., … & Murray, C. J. (2019). Health effects of dietary risks in 195 countries, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. The lancet, 393(10184), 1958-1972.

[3] Babalola, F., Adesuyi, A., David, F., Kolajo, B. B. A., Urhi, A., Akinade, O., … & Anugwom, G. O. (2022). A comprehensive review on the effects of vegetarian diets on coronary heart disease. Cureus, 14(10).

Researchers have discovered a compound and a brain region that may be related to chronic pain in older people and published their findings in Aging Cell.

When one sense doesn’t decline

Aging destroys the senses over time, most notably sight and hearing [1]. Sensations related to touch are diminished as well, including cold, heat, movement, and vibration [2].

Pain, most notably, is not among the diminished senses. Instead, aging is largely associated with chronic pain, some of which can be attributed to chronic conditions such as arthritis [3]. Other research involving the primary somatosensory cortex (S1), a key brain region involved in the processing of pain signals [4], has found that pain inhibition pathways are reduced with aging [5].

Previous work has also found that PGC-1α, a compound involved in mitochondrial formation and function, also plays a role in the function of neurons, including the neurons involved in pain processing [6]. However, the relationship between PGC-1α, the S1, pain, and aging had not been fully explored.

Why younger animals recover more quickly from pain

The researchers examined populations of wild-type Black 6 mice, one at 4 weeks of age and another at 18 weeks of age, finding that the younger mice expressed nearly triple the amount of PGC-1α as the older mice did. These mice were then injured by constricting their sciatic nerves leading to their hind legs. The older mice took longer to recover from this injury, being more sensitive to touch stimuli and for a longer period of time. The researchers refer to this as ‘aging-associated pain chronification’.

To further examine this relationship, the researchers created a population of mice that had only one functional allele of PGC-1α, compared to normal mice that have two. (Mice with no copies of PGC-1α die very early of neurodegeneration.) At 4 weeks of age, both populations of mice sustained the same injury as in the previous experiment, and the mice with reduced PGC-1α fared even worse than the older mice, failing to fully recover within seven weeks. Male and female mice had similar results.

The brains of younger and older mice were also investigated after leg injury. At day 7, both younger and older mice had similar levels of activity in S1 excitation neurons; however, by day 35, this increased excitation had largely ceased in the younger animals but was still significantly more active in the older ones. Interneurons, which connect the S1 to the rest of the brain, had less activity at day 7 in both younger and older animals, but this was restored at day 35 only in the younger ones. Further experiments using highly specific drugs found that more interneuron activity resulted in behaviors suggesting less chronic pain.

Using an adeno-associated virus (AAV) to increase the production of PGC-1α in older animals reduced their chronic pain after injury approximately to the levels shown by younger animals. Also, just like in younger animals, the excitation neuron activity was decreased and the interneuron activity was increased at day 35 after injury.

These results demonstrate that the chronic pain associated with aging isn’t always attributable to a chronic condition such as arthritis. Rather, it can be attributed to an age-related decline in a crucial brain function, and future therapies that focus on restoring this function may become a key part of ameliorating this pain.

Literature

[1] Cavazzana, A., Röhrborn, A., Garthus-Niegel, S., Larsson, M., Hummel, T., & Croy, I. (2018). Sensory-specific impairment among older people. An investigation using both sensory thresholds and subjective measures across the five senses. PloS one, 13(8), e0202969.

[2] Dunn, W., Griffith, J. W., Sabata, D., Morrison, M. T., MacDermid, J. C., Darragh, A., … & Tanquary, J. (2015). Measuring change in somatosensation across the lifespan. The American Journal of Occupational Therapy, 69(3), 6903290020p1-6903290020p9.

[3] Marks, R. (2018). Successful aging and chronic osteoarthritis. Medicines, 5(3), 105.

[4] Ding, W., Yang, L., Chen, Q., Hu, K., Liu, Y., Bao, E., … & Shen, S. (2023). Foramen Lacerum impingement of trigeminal nerve root as a rodent model for trigeminal neuralgia. JCI insight, 8(11).

[5] González-Roldán, A. M., Terrasa, J. L., Sitges, C., van der Meulen, M., Anton, F., & Montoya, P. (2020). Age-related changes in pain perception are associated with altered functional connectivity during resting state. Frontiers in Aging Neuroscience, 12, 116.

[6] Miao, Z. F., Adkins-Threats, M., Burclaff, J. R., Osaki, L. H., Sun, J. X., Kefalov, Y., … & Mills, J. C. (2020). A metformin-responsive metabolic pathway controls distinct steps in gastric progenitor fate decisions and maturation. Cell Stem Cell, 26(6), 910-925.

Scientists have demonstrated that viral particles from a harmless plant virus can be used as an adjuvant therapy to prevent recurrence of disease and metastasis formation in several cancer models [1].

The challenge of keeping cancer at bay

Medicine’s progress in treating cancer has been patchy: impressive with some cancers, dead-slow with others. For instance, metastatic cancer remains a major problem, as a cancer’s metastasis dramatically lowers the survival rate. Up to 90% of all cancer-related deaths are attributed to metastases [2].

After a primary treatment, such as surgery, adjuvant therapies are given to lower the risk of the cancer coming back. These treatments can include chemotherapy, radiation therapy, and immunotherapy and aim to eliminate any remaining cancer cells and not let them engender metastases. However, even when successful, adjuvant therapies often cause powerful side effects that reduce life quality and are associated with shorter lifespans [3].

One promising novel approach to preventing metastases is oncolytic viruses, which attack cancer cells while supposedly sparing healthy cells [4]. They can cause lysis (cellular death) and/or recruit to the tumor the patient’s immune system, which recognizes the virus as a foreign pathogen. When immune cells arrive at the site, they also attack cancer cells.

Switching to “vegan” viruses

However, existing viral therapies are still not specific enough and can harm non-cancer cells. To overcome this problem, a team from the University of California in San Diego has been developing a treatment based on a plant virus. In their previous studies, the researchers showed that the cowpea mosaic virus that infects black-eyed peas can recruit the immune system when injected directly to the tumor microenvironment without actually infecting any cells, cancer or not [5]. Since the virus does not kill cells directly, precise local administration might not be needed, which was the hypothesis that the researchers tested this time.

Not all plant viruses elicit immune responses in humans. In fact, the researchers tested several other viruses and found cowpea mosaic virus particles (CMVPs) to be exceptional in this regard. The team then tested CMVPs on a mouse model of colon cancer. Intraperitoneal cancers are among the deadliest and tend to metastasize quickly. Mice were injected with a dose of CMVPs and, one week later, challenged with an injection of colon cancer cells.

The treated mice demonstrated dramatically improved survival over untreated controls. 56% of the animals in the study group survived, while all mice in the control group succumbed to the disease within 25 days. On average, the treatment slowed tumor growth almost to a halt.

To see whether the treatment provided long-term protection, 40 days into the experiment, the surviving mice were re-challenged with a new dose of cancer cells. A subset of those mice was also injected with T cell-neutralizing antibodies to investigate the importance of T cells for any possible anti-tumor effect. The mice with their T cells intact showed robust survival, unlike those that had their T cells neutralized.

When another group of survivors were injected with cancer cells away from the original injection site, the protection remained robust, suggesting a systemic and tissue-agnostic nature. “Overall, the re-challenge experiments demonstrate that CPMV prophylaxis generates potent immune memory after initial challenge that is tumor-specific, but tissue-agnostic”, the paper says.

Effective in other cancers too

In cimilar experiments, the treatment proved effective against ovarian and breast cancer. The researchers also specifically analyzed lung metastases in a melanoma model, as lung metastases appear in many cancers, resulting in poor prognosis and low survival rates. The treatment effectively prevented melanoma cells from metastasizing into the lungs.

All these experiments were designed to mimic an adjuvant treatment aimed at preventing the recurrence and metastasis of cancer. However, people with intraperitoneal cancer often already have metastases when they are first diagnosed. To address this situation, the researchers reversed the order of things, first challenging mice with a small dose of cancer cells and waiting a week to administer this treatment, which was found to still be effective. In another experiment, they let the cancer progress and then surgically removed the tumors before administering CMVP particles. The results were still impressive, with the number of long-term survivors increasing fourfold.

“Even if you perform surgery to remove the tumors, no surgery is perfect and there is outgrowth of metastasis if no additional treatment is provided,” said Nicole Steinmetz, a professor of nanoengineering at UCSD and the study’s leading author. “Here, we use our plant virus nanoparticles after surgery to boost the immune system to reject any residual disease and prevent circulating tumor cells from metastatic seeding. We found that it works really, really well!”

Literature

[1] Chung, Y. H., Zhao, Z., Jung, E., Omole, A. O., Wang, H., Sutorus, L., & Steinmetz, N. F. (2024). Systemic Administration of Cowpea Mosaic Virus Demonstrates Broad Protection Against Metastatic Cancers. Advanced Science, 2308237.

[2] Guan, X. (2015). Cancer metastases: challenges and opportunities. Acta pharmaceutica sinica B, 5(5), 402-418.

[3] Beisecker, A. E., Cook, M. R., Ashworth, J., Hayes, J., Brecheisen, M., Helmig, L., … & Selenke, D. (1997). Side effects of adjuvant chemotherapy: perceptions of node‐negative breast cancer patients. Psycho‐Oncology: Journal of the Psychological, Social and Behavioral Dimensions of Cancer, 6(2), 85-93.

[4] Shalhout, S. Z., Miller, D. M., Emerick, K. S., & Kaufman, H. L. (2023). Therapy with oncolytic viruses: progress and challenges. Nature Reviews Clinical Oncology, 20(3), 160-177.

[5] Wang, C., & Steinmetz, N. F. (2020). A combination of cowpea mosaic virus and immune checkpoint therapy synergistically improves therapeutic efficacy in three tumor models. Advanced functional materials, 30(27), 2002299.